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From: http://www.hcvadvocate.org/hcsp/articles/gish-2.html

Minimizing the Impact of Neuropsychiatric Effects During Chronic HCV Disease
and Treatment

Robert G. Gish , M.D.

(To see the figures and illustrations in this article, please download the
pdf version.)

New data are emerging that implicate direct effects of the hepatitis C virus
(HCV) on the central nervous system, along with side effects of both
peginterferon and ribavirin as causes of multiple symptoms during treatment
of HCV. Neuropsychiatric symptoms are of great concern in patients with
hepatitis C because they are common, may reduce quality of life, and can
limit treatment adherence and effect the outcome of treatment. To improve
patient well-being and the likelihood of successful anti-HCV therapy, it is
critical that physicians screen patients for neuro-psychiatric symptoms and
manage these problems and symptoms proactively.

Pre-existing neuro-psychiatric symptoms are common in hepatitis C patients.
In fact, 35% to 57% of patients with chronic HCV infection may have
depression upon diagnosis or before starting any therapy. Furthermore, new
neuropsychiatric symptoms emerge in an additional 30% to 40% of patients
receiving peginterferon / ribavirin treatment. Cognitive deficits,
particularly those affecting concentration, memory, and psychomotor speed,
have been identified in patients with even mild HCV infection as well.

The pathophysiology of these toxic effects of HCV remain poorly defined. One
theory is that HCV may infect the brain via macrophage or microglial cells.
Another is that toxins may accumulate in the blood secondary to impaired
clearance by a cirrhotic liver, causing impaired cognition. Cirrhosis may be
predictive of poorer cognitive function due to clinical or subclinical
encephalopathy, and progressive hepatic injury in the HCV-infected patient
without cirrhosis also may play a role in the development of neurocognitive
problems although this is rarely seen in patients without significant
fibrosis and portal hypertension. Antiserotonergic effects of interferon
have been proposed as a mechanism in the development of interferon-related
depression and may explain why patients symptoms from interferon therapy can
be profoundly improved with SSRI type antidepressants.

A recent prospective cohort study found that although only 11% of patients
treated with peginterferon/ribavirin met criteria for major depression, yet
more than one third developed symptoms of moderate to severe depression
during treatment. Whereas interferons are generally known to be associated
with psychiatric side effects, this study was one of the first to identify a
dose-related association between PEG interferon/ribavirin treatment and
depression.

Due to the chronic nature and nonspecific symptoms of HCV infection,
distinguishing the somatic complaints of disease chronicity from a
depressive syndrome is a major clinical challenge. Patients with major
depression often feel ill, experiencing somatic and/or cognitive symptoms
and a perceived state of "brain fog" and other symptoms that impair the
patients functional level. These symptoms can easily be confounded by the
presence of a chronic HCV infection. Nonsomatic symptoms of depression may
include low self-esteem, feelings of guilt, worthlessness, hopelessness, and
in the most severe cases, suicidal ideation. Some depression screening
tools-such as the Hospital Anxiety and Depression Scale (HADS)-are geared
toward assessment of nonsomatic symptoms of depression, and may be useful in
HCV-infected patients who exhibit symptoms of major depression. The Center
for Epidemiologic Studies of Depression (CES-D) self-administered scoring
sheet also may be useful in an office practice.

The impact of depression on the patient can be significant, causing
irritability, fatigue, apathy, lack of concentration, and in extreme
situations, suicidal ideation or suicide. It is therefore not surprising
that depression can have a negative impact on adherence to anti-HCV therapy.
Moreover, another prospective cohort study found a correlation between
depression symptoms and clearance of HCV RNA at week 24, even after
adjusting for ribavirin dose assignment, genotype, age, antidepressant
usage, dose reduction of peginterferon or ribavirin, and knowledge of viral
status during treatment. Periodic assessment for depression during treatment
is imperative, with expert psychiatric referral provided as needed if signs
and symptoms of depression progress during treatment.

Profound improvement can be achieved with antidepressant pharmacotherapy and
formal psychotherapy for treatment of depression. There are no
placebo-controlled studies evaluating the treatment of interferon-induced
depression. An open-label trial of citalopram conducted in 15 patients with
HCV infection demonstrated a significantly positive response in
interferon-treated patients. Prophylactic therapy in patients with a recent
or remote history of depression may be controversial; but recent studies
have shown a benefit and proactive antidepressant therapy is strongly
advised in clinical practice, both from this author's clinical experience
and from surveys of practitioners who manage HCV treatment. Patients with
major depression may also benefit from support groups, but this should not
be a replacement for pharmacologic therapy and psychotherapy.

Pharmacologic guidelines for general treatment of neuropsychiatric disorders
may offer the best approach to managing depression in the
peginterferon-treated patient. These guidelines emphasize individualized
selection of an agent, often exploiting the side-effect profile of the
various medications available. For example, agents that promote sleep may be
most appropriate for patients who have a primary sleep disturbance, whereas
patients experiencing fatigue may benefit most from activating agents.

Patients with a history of major depression or significant depressive
symptoms including history of suicide attempts, or bipolar disorder or
psychosis, should be referred for expert psychiatric diagnosis and
management prior to treatment initiation. Patients with a pre-existing
history of bipolar disorder should be monitored closely while receiving
interferon therapy, and, whenever possible, treated prophylactically with a
mood stabilizer such as olanzapine or quetiapine (lithium or valproic acid
can also be considered, with close follow-up). Any patient for whom the
medical practitioner is not comfortable starting antidepressant therapy
should be referred for clearance before starting anti-HCV treatment, and
psychiatric follow-up should continue periodically during therapy.

In summary, neuropsychiatric symptoms are common in HCV-infected patients
both at baseline and as side effects of peginterferon therapy. Without
appropriate intervention, these symptoms can have serious consequences for
the patient and can also limit adherence to, and therefore success of,
antiviral therapy. Fortunately, depression and other neuropsychiatric side
effects can generally be managed effectively with available pharmacologic
therapies, thereby allowing patients to stay on anti-HCV therapy with the
best chance of treatment success.

Important References

(truncated for brevity, go to hcvadvocate for long list of footnotes)

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